Our goal is to create a compact, affordable, fully automated, screening system for large-scale drug 2 testing in living small animal disease models (e.g., worms, flies, and fish). Modern drug discovery is 3 driven by high-throughput screening (HTS) systems that have the capacity to evaluate large chemical 4 compound 'libraries'. The majority of hits identified by in vitro HTS assays fail at animal testing stages 5 after significant investments in time and costs have already been made. This increase drug 6 development costs and presents a critical barrier to the discovery of novel therapies. A solution to this 7 problem is to integrate small animal disease models into HTS platforms at the earliest stage of the 8 discovery process. Powerful 'high-content' in vivo screening systems use automated imaging 9 processes to collect phenotypic data following drug exposures. However, these methods cannot attain 10 true HTS capacities and therefore cannot fully address current drug discovery bottlenecks. To address 11 the unmet need for true HTS whole-organism screening systems, we adapted small animal model 12 assays to standard HTS instrumentation to create Automated Reporter Quantification in vivo (ARQiv) 13 systems. ARQiv is a versatile drug discovery and development platform for quantifying reporter levels in 14 living organisms. ARQiv is: 1) Rapid-capable of true HTS/ultra-HTS capacities, 2) Reproducible- 15 attaining HTS-compatible assay quality, and 3) Flexible-can temporally resolve any reporter-based 16 assay that can be deployed in vivo, allowing monitoring of developmental and/or disease 17 progression/remission. Here we propose to prototype and validate compact, affordable, fully 18 automated, robotics-integrated, ARQiv systems intended be sold as bench top whole- organism HTS 19 screening platforms. At the conclusion of Phase II, three product lines will be ready for production 20 (ARQiv-1, 2, and 3); the most sophisticated option, ARQiv-3, will facilitate screening a variety of small 21 animal model species. Union Biometrica, a leader in whole-organism screening technologies will 22 market ARQiv to academic and commercial customers; ARQiv systems will be retailed alongside their 23 COPAS(tm), BioSorter(r), and VAST BioImager(tm) products due to the high degree of complementary 24 synergy between ARQiv and these systems. Here, we will validate robotics-integrated prototypes of 25 ARQiv-1 and ARQiv-2 systems by achieving three milestones designed to test specific strengths these 26 platforms brings to whole-organism screening: 1) achieve true HTS true rates (50,000 27 individuals/day), 2) optimize in vivo assay quality by incorporating 'best practice' methodologies such as 28 quantitative HTS (qHTS) and longitudinal dual-reporter detection and, 3) establish methods for 29 offsetting losses in throughput that attend complex phenotyping assays.